Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis

Abstract

Many clinical trials have investigated the role of ICIs in PM, with contrasting results. We performed a systematic review and meta-analysis of clinical trials testing single-agent anti-Programmed Death -1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or combined treatment in PM patients, analyzing response and survival rate as well as safety data. We selected 17 studies including 2328 patients. Both OS and PFS rates were significantly higher with combined ICI treatments than with single agent anti-PD-1/PD-L1 (p < 0.001 and p = 0.006, respectively) or anti CTLA-4 (p < 0.001) treatments. ORR and DCR for all ICI treatments were 20% (95% CI 13–27%) and 56% (95% CI 45–67%), respectively, and they did not significantly differ between combined and single agent treatments (p = 0.088 and p = 0.058, respectively). The 12-month OS and 6-month PFS rates did not differ significantly (p = 0.0545 and p = 0.1464, respectively) among pre-treated or untreated patients. Combined ICI treatments had a significantly higher rate of Adverse Events (AEs) (p = 0.01). PD-L1-positive patients had a higher probability of response and survival. In conclusion, combined ICI treatments have higher efficacy than single agents but are limited by higher toxicity. Efficacy was independent of treatment line, so a customized sequential strategy should still be speculated. PD-L1 expression could influence response to ICIs; however, reliable biomarkers are warranted.

Role of Durvalumab (Anti-PD-L1) in the Management of Mesothelioma: A Systematic Review of the Current Literature

“…Nevertheless, PFS and OS rates did not significantly differ whether ICIs were administered as the first or subsequent lines of treatment. This is intriguing given the grim prognosis of pleural mesothelioma and the absence of effective second-line therapies, prompting speculation about potential sequential approaches [18]. Durvalumab has also been explored in combination with other agents.…”

“…There is a pressing necessity for predictive factors to identify patients who would benefit from this approach. As suggested by the Checkmate 743 trial, a sequential strategy involving platinumpemetrexed chemotherapy followed by single-agent anti-PD-1/PD-L1 therapy upon disease progression may still be considered, particularly in epithelioid pleural mesothelioma patients who do not significantly benefit from ICI combinations [11,18].…”

Current State-of-the-Art Therapy for Malignant Pleural Mesothelioma and Future Options Centered on Immunotherapy

“…Finally, in a meta-analysis of 29 publications, PD-L1-positive patients who did not receive immunotherapy appeared to have a worse prognosis compared to PD-L1-negative patients [38]. In contrast, among patients who received immunotherapy, similar or better survival was observed among PD-L1-positive individuals.…”

Antitumoral effects of Bortezomib in malignant mesothelioma: evidence of mild endoplasmic reticulum stress in vitro and activation of T cell response in vivo

“…A small benefit in terms of increased survival can be obtained with the addition of the Vascular Endothelial Growth Factor inhibitor Bevacizumab to the previous regimen, allowing a median survival of 19 months vs. the 16 months achieved with platinum agents/folates alone [ 1 ]. MM is further characterized by an immunosuppressive microenvironment, and modest response rates have been obtained with immunotherapy approaches, including those based on the recently introduced Immune Checkpoint Inhibitors (ICIs) [ 1 , 2 , 5 , 8 , 9 ]. The low efficacy of current treatment options highlights the urge to identify more effective therapies aimed at improving MM patients’ survival.…”